1. Field of the Invention
This invention relates to an anti-inflammatory analgesic cataplasm comprising indomethacin as the active ingredient, and to a process for the production of such cataplasm.
2. Description of the Prior Art
Indomethacin is a compound represented by the following formula ##STR1## and made on record in "The Pharmacopoeia of Japan", 9th Edition. Indomethacin is known to be a non-steroid antiinflammatory drug exhibiting anti-inflammatory and analgesic activities.
As a formulation, indomethacin has been commercially available in the form of a capsule since 1966 and has found wide use for the medical treatment of rheumatoid arthritis and arthritis deformans as well as various inflammatory diseases and postoperative inflammations. Indomethacin has thus been proven to be substantially medicinally effective. When administered orally, however, indomethacin encounter many adverse effects of gastroenteric troubles such as decreased appetite, nausea, vomiting, indigestion, diarrhoea and stomach ache as well as central nervous system troubles such as frontal head ache, drowsiness, dizziness and mental disorders.
An alternative formulation resides in an indomethacin suppository for parenteral administration. Although the suppository reduces the gastroenteric troubles experienced with the capsule just discussed, it cannot be applied to a patient sufferring from an intestinal disease, nor does it overcome the central nervous system troubles caused by the systemic circulation of indomethacin.
An indomethacin ointment has been developed so as to be rendered suitable for a more advanced mode of application which would avoid the central nervous system troubles and achieve any local effectiveness of indomethacin. Such ointment in fact minimizes the adverse effects noted above but is not still satisfactory in that the amount of application is difficult to hold at a constant level because of the user's arbitrary choice of dosage. Moreover, a solvent contained in the ointment is liable to evaporate during or after the application, resulting in varied formulation, so that indomethacin is hard to be absorbed through the skin and does not provide its inherently desired potency. Further inconvenience is that the user's fingers are soiled with the ointment during its application to an affected part, with eventual staining of his clothes after the application.
In many studies leading to the present invention, particular note has been taken of the fact that the absorption rate and amount of indomethacin through the skin depend largely upon the application amount and surface area of this medicine relative to any affected parts.
On the other hand, indomethacin is not subject to percutaneous absorption since a horny substance layer or stratum corneum of the skin acts as a first barrier to prevent evaporation of water and penetration of any substance from the outside and since a basal cell layer of the skin also acts as a second barrier to obstruct percutaneous absorption. Hydration of the stratum corneum can increase the penetrability of the skin by four to five times as much as usual, and hence, such hydration constitutes an important factor for percutaneous absorption of indomethacin.
It is necessary, therefore, that a substantial amount of water be added relative to a proportion of indomethacin to improve the absorbability of the medicine for use in a cataplasm.
However, indomethacin is an acidic anti-inflammatory drug (pKa 4.5) which is insoluble in water but is soluble in an alkaline solution. When dissolved in an alkaline solution, indomethacin becomes chemically unstable and readily decomposable. It is difficult to prepare an indomethacin-containing cataplasm by any conventional method employing a weakly alkaline solution. Even if mixed with and suspended in any base components, indomethacin is less stable and less absorbable through the skin in a pH range of 7 or higher wherein it is ionized. And yet, no medical treatment by indomethacin is attainable with satisfactory results.